Abstract
Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 652-665 |
| Number of pages | 14 |
| Journal | Nuclear Medicine and Biology |
| Volume | 39 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jul 1 2012 |
| Externally published | Yes |
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Keywords
- [F]FLT
- Click chemistry
- Fluorine-18
- Nucleosides
- Proliferation
ASJC Scopus subject areas
- Molecular Medicine
- Radiology Nuclear Medicine and imaging
- Cancer Research
Cite this
Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. / Smith, Graham; Sala, Roberta; Carroll, Laurence; Behan, Kevin; Glaser, Matthias; Robins, Edward; Nguyen, Quang Dé; Aboagye, Eric O.
In: Nuclear Medicine and Biology, Vol. 39, No. 5, 01.07.2012, p. 652-665.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and evaluation of nucleoside radiotracers for imaging proliferation
AU - Smith, Graham
AU - Sala, Roberta
AU - Carroll, Laurence
AU - Behan, Kevin
AU - Glaser, Matthias
AU - Robins, Edward
AU - Nguyen, Quang Dé
AU - Aboagye, Eric O.
PY - 2012/7/1
Y1 - 2012/7/1
N2 - Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.
AB - Introduction: Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining. Methods: N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo. Results: Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (~8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent. Conclusions: The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.
KW - [F]FLT
KW - Click chemistry
KW - Fluorine-18
KW - Nucleosides
KW - Proliferation
UR - http://www.scopus.com/inward/record.url?scp=84862809233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862809233&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2011.12.002
DO - 10.1016/j.nucmedbio.2011.12.002
M3 - Article
C2 - 22321533
AN - SCOPUS:84862809233
VL - 39
SP - 652
EP - 665
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
SN - 0969-8051
IS - 5
ER -